Animal feed and process

ABSTRACT

AN ANIMAL FEED FOR INCREASING MEAT, MILK OR EGG PRODUCTION COMPRISING A COMPOUND OF THE GROUP CONSISTING OF A 1-SUBSTITUTED-6-PHENYL-4H -S- TRIAZOLO (4,3-A)(1,4) BENZODIAZEPINE OF THE FORMULA:   1-(X-CH(-R0)-),4-R1,6-(R2,R3-PHENYL),R4,R5-4H-S-TRIAZOLO   (4,3-A)(1,4)BENZODIAZEPINE   WHEREIN R0 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, METHYL, ETHYL, FLUORINE, CHLORINE, AND BROMINE; WHEREIN X IS FLUORINE, BROMINE, OR CHLORINE; WHEREIN R1 IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND ALKYL OF 1 TO 3 CARBON ATOMS, INCLUSIVE; AND WHEREIN R2, R3, R4, AND R5 ARE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, ALKYL AS DRFINED ABOVE, HALOGEN, NITRO, CYANO, TRIFLUOROMETHYL, AND ALKOXY, ALKYLTHIO, ALKYLSULFINYL, AND ALKYLSULFONYL, IN WHICH THE CARBON CHAIN MOIETIES ARE OF 1 TO 3 CARBON ATOMS, INCLUSIVE AND A PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALT THEREOF IN COMBINATION WITH NUTRIENT FEEDS.

United States Patent Office 3,836,660 Patented Sept. 17, 1974 3,836,660 ANIMAL FEED AND PROCESS Robert J. Collins, 7127 Winter Forest Drive, Portage, Mich. 49081 No Drawing. Filed Aug. 9, 1971, Ser. No. 170,273 The portion of the term of the patent subsequent to Sept. 17, 1991, has been disclaimed Int. Cl. A61k 27/00 US. Cl. 424-269 6 Claims ABSTRACT OF THE DISCLOSURE An animal feed for increasing meat, milk or egg production comprising a compound of the group consisting of a 1-substituted-6-phenyl-4H s triazolo[4,3-a][1,4] benzodiazepine of the formula:

Rn x-d N 5 m RI Formula 1 wherein R is selected from the group consisting of hydrogen, methyl, ethyl, fluorine, chlorine, and bromine; wherein X is fluorine, bromine, or chlorine; wherein R is selected from the group consisting of hydrogen and alkyl of 1 to 3 carbon atoms, inclusive; and wherein R R R and R are selected from the group consisting of hydrogen, :alkyl as defined above, halogen, nitro, cyano, trifluoromethyl, and alkoxy, alkylthio. alkylsulfinyl, and alkylsulfonyl, in which the carbon chain moieties are of 1 to 3 carbon atoms, inclusive and a pharmaceutically acceptable acid addition salt thereof in combination with nutrient feeds.

CROSS REFERENCE TO RELATED APPLICATIONS This application is related to copending United States application Ser. No. 138,288, filed Apr. 28, 1971, which discloses compounds of the Formula 1 and methods for their preparation.

BRIEF SUMMARY OF THE INVENTION Broadly the present invention encompasses a nutritionally adequate animal feed having dispersed therein a compound of the Formula 1 in sufficient concentration to provide increasing productivity and feed efficiencies in healthy meat-producing, milk-producing or egg-laying animals. The invention also includes the process of feeding the composition to meat-producing, milk-producing or egg-laying animals.

DETAILED DESCRIPTION It has been found in recent years that meat-producing animals will gain more weight and gain it faster when various classes of compounds such as vitamins, minerals, estrogens, antibiotics, and tranquilizers are added to the diet. Although the presently available compounds are useful, new materials are still being sought that would produce weight gains more rapidly, to a greater extent, more efiicientlywith respect to feed intake at a lower cost and without undesirable side effects.

It is now possible by use of the present invention to obtain unexpected results in the feeding of meat-producing, milk-producing, or egg-laying animals; that is to say,

an increased rate of weight gain, an increased amount of weight gain, an increase in milk production, or increased rate of egg laying, as well as increased feed efficiency, can be obtained by the addition of minute quantities of a gompound of the Formula 1 to the animals usual nutrient eed.

Compounds of the Formula 1 can be prepared by methods disclosed in United States application Ser. No. 138,288, filed Apr. 28, 1971.

Unless otherwise specified, all percentages are given on a weight-to-weight basis. The pound (1b.) weights given are avoirdupois units.

Feeding of the compositions of the present invention can commence for birds shortly after hatching and in the case of mammals, during the creep-feeding period of suckling animals when they are starting on solid food and, of course, after weaning. Feeding of the compositions is continued throughout the growing period, lactation period, or egg-laying period.

The total concentration of the compound of the Formula 1 in the feed composition is determined with regard to the species of animal, age, weight, and average amount of feed consumed daily. Preferably the compound of the Formula. l is employed in the finished feed that will supply the animal with a daily intake of from about 0.3 mg. to about 500 mg. per head per day.

The following table illustrates the range of compound of Formula 1 in milligrams daily dose per head per day for representative animals.

The foregoing dosage can generally be accomplished by providing from about 250 mg. to about 25,000 mg. of a compound of the Formula 1 per ton of finished feed.

Advantageously a compound of the Formula 1 is supplied in the form of a liquid or solid premix wherein the concentration is -2000 times greater than the desired final concentration of the feed. For example, the compound of Formula 1 can be dissolved or suspended in a fluid vehicle such as corn oil, cottonseed oil, molasses, distillers solubles and the like to prepare a fluid premix. Alternatively, a solid premix can be prepared by mixing a compound of the Formula 1 with an edible solid diluent such a sucrose, lactose, starch, corn meal, flour, calcium carbonate, soybean meal and the like.

Example 1 1 Contains the following percent of minerals: Mn, 12; Co. 0.08 Fe, 5.0; Cu, 0.4 I, 0.24:; Zn, 0.7.

The above feed to be mixed, pelleted and offered to fattening lambs free-choice in conjunction with hay.

j To 999 partssof .the preceding feed isadded 1' part of a p emi omp sit a r r y mix -4 smo 8-chloro-1-(l-chloroethyl) 6 phenyl 4H s triazolo- [4,3-a][1,4]benzodiazepine with sufficient corn meal to make one pound.

The feedingv composition so prepared supplies 1.4 mg. of 8-chloro l (1 chloroethyl)-6-phenyl-4H-s-triazolo- [4,3-a][1,4]benzodiazepine per pound or 3.1 parts per million.

The foregoing composition is usefully fed to lambs for increased rate of weight gain and improved utilization of feed.

Example 2 A chicken feed for broilers is prepared from the following types and amounts of ingredients:

Percent Yellow corn meal 67.35 Soybean oil meal 24.00 Menhaden fish meal 6.00 Steamed bone meal 1.00 Ground limestone 1.00 Iodized salt .34 25% Choline chloride .13 Vitamin B supplement (6 mg./lb.) .10 Manganese sulfate .02 Supplemental vitamin mix 1 .06

Consisting of 16.0 gm. Vitamin A supplement (10 units/ mg.); 3.6 gm. Vitamin D3 supplement (10,000 unitslgmg; 7.1 gm, riboflavin supplement (1 gm. riboflavin per ounce 500 mg. niacin.

A fattening feed for 800 pound yearling cattle is prepared from the following types and amounts of ingredients:

Percent Ground ear corn 89.75 Soybean oil meal, 44% 9.0 Ground limestone 0.7 Salt 0.5 Trace mineral mixture 1 0.05

1 Contains the following percent of minerals: Mn, 12; Co, 0.08; Fe, 5.0; Cu, 0. 1; I, 0.24 Zn, 0.7

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 3.0 gm. of 8-chloro 1 (l-chloroethyl) 6 phenyl-4H-s-triazolo- [4,3-a] [1,4]benzodiazepine with sufiicient wheat flour to make 1 pound.

The feeding composition so prepared supplies 3.0 mg. of 8-chloro-1-(1-chloroethyl)-6-phenyl 4H s triazolo- [4,3-a] [1,4]benzodiazepine per pound, or about 6.6 parts per million.

Cattle are to receive the foregoing feed ad libitum together with lbs. of hay per head per day and when so fed have an increased rate of weight gain and improved utilization of feed.

I k Example 4 'A swinediet for growing hogs of 40"to' pounds body weight is prepared from the following types and amounts of ingredients:

Percent Corn ground 78.15 Soybean oil meal, 44% 17.0 Meat and bone scraps, 50% 3.0 Oyster shell flour 0.4 Bone meal 0.5

Salt 0.5 Trace mineral mixture 1 0.05 Zinc oxide 0.01 Vitamin A and D supplement 2 0.25 B Vitamin supplement 3 0.05 Vitamin B supplement 0.09

1 Contains the following percent of minerals: Mn, 12; Co, 0.08; Fe, 5.0; Cu, 0.4 I, 0.24 Zn, 0.7.

2 Contains 300 USP units Da/gm. and 1500 I.U.A./gm.

3 Contains per lb. 2 riboflavin, 2000 mg. calcium pantothenate, 4000 mg.; niacin, 9000 mg.; and choline chloride 10,000 mg.

* Contains 6 mg. Vitamin B12 per lb.

To 999 parts of the preceding feed is added 1 part of a premix composition prepared by mixing 1.5 gm. of 8-chloro 1 (l-chloroethyl) 6 phenyl-4H-s-triazolo- [4,3-a][1,4]benzodiazepine with sufficient ground limestone to make one pound.

The feeding composition so prepared supplies 1.5 mg. of 8-chloro-1-(l-chloroethyl)-6-phenyl-4H s triazolo [4,3-a]-[1,4]benzodiazepine per pound, or about 3.3 parts per million.

The foregoing composition is usefully fed to hogs for increased rate of weight gain and improved utilization of feed.

Example 5 Following the procedure of the preceding Examples 1 to 4, inclusive, animal feeds are similarly prepared substituting equimolar amounts of:

8-chloro-l-(dichloromethyl)-6-phenyl-4H s triazolo- [4,3-a] [1,4]benzodiazepine; 8-chloro-1-(bromomethyl)-6-phenyl-4H s triazolo[4,3-

a] [1,4] benzodiazepine; 8-chloro-1-(1-chloromethyl)-6-phenyl 4H s triazolo- [4,3-a] [1,4]benzodiazepine; 8-fluoro-l-(dibromomethyl)-6-(o-chlorophenyl) 4H striazolo [4,3-a] [1,4] benzodiazepine; 7,8-dicyano-1-(a-chloroethyl)-6-(o-bromophenyl) 4H-striazolo [4,3-a] [1,4] benzodiazepine; 8-chloro-1-(chloromethyl)-6-(o chlorophenyl) 4H striazolo [4,3-a] [1,4] benzodiazepine; 8,10-dimethyl-l- (fluoromethyl) 6 [p (methylthio) phenyl] -'4H-s-triazolo [4,3-a] 1,4]benzodiazepine;

s-triazolo[4,3-a] [1,4] benzodiazepine; 8-nitro-1-(bromomethyl)-6-(o-chlorophenyl)-4H-s triazolo4,3-a] [1,4] benzodiazepine; 1-dichloromethyl-7-trifiuoromethyl-9 propylsulfonyl 6- (p-ethoxyphenyl)-4H s triazolo[4,3-a][l,4]benzodiazepine; 8-chloro-6-phenyl-4H-s-triaz0lo[4,3 a] [l,4]benzodiazepine-l-acetonitrile; 8-chloro-1-[(diethylamino)methyl]-6-phenyl-4H-s tria zolo[4,3-a] [1,4] benzodiazepine; 8-chloro-1-(ethylthio)-6-phenyl-4H-s triazolo[4,3 a]- 1,4] benzodiazepine; S-trifluoromethyl-l-(propylthio)-6 (o chlorophenyl)- 4H-s-triazolo[4,3-a] [1,4]benzodiazepine for the 8-chlorol-(l-chloroethyl)-6-phenyl-4H s triazolo[4,3-a][l,4] benzodiazepine of the examples.

I claim:

1. A process for increasing meat, milk, or egg production in a healthy meat-producing, milk-producing or egglaying animal comprising the feeding thereto of from about 0.03 to about 500 mg./day of a compound selected from the group consisting of a 1-substituted-6-pheny1-4H- s-triazolo[4,3-a][1,41benzodiazepine of the formula:

R N 16% N 6 ceptable acid addition salt thereof in combination with the nutrient feed.

2. The process of claim 1 wherein the member selected is in a concentration of from 250 mg. to 25,000 mg. per pound of nutrient carrier in the form of a premix.

3. The process of claim 1 when the member selected is in the concentration from 500 mg. to 50,000 mg. per ton of feed.

4. The process of claim 1 wherein the compound is 8- chloro-l-(l-chloroethyl)-6-phenyl-4H s triazolo[4,3-a] [1,4] benzodiazepine.

5. The process of claim 2 wherein the compound is 8- chloro-1-( l-chloroethyl)-6-phenyl-4H s triazolo [4,3-a] [1,41benzodiazepine.

6. The process of claim 3 wherein the compound is 8- chloro-1-( l-chloroethyl)-6-phenyl-4H s triazolo[4,3-a] [1,4] benzodiazepine.

OTHER REFERENCES 1. of Medicinal and Pharmaceutical Chemistry, Vol. 1, #2, 1959, pp. 121-122.

ALBERT T. MEYERS, Primary Examiner F. E. WADDELL, Assistant Examiner 

